Design and Synthesis of 3-Arylmethylene-1H-quinoline-2,4-dione Derivatives as Potential Hepatitis C Virus RNA Polymerase Inhibitors

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Hepatitis C virus (HCV) has become a serious etiological agent worldwide. HCV sets up a persistent infection in 70-80% of cases, and can lead to cirrhosis or hepatoma. Currently available interferon-based treatments show limited efficacy. Therefore, to develop new and more effective therapies is a vital and urgent issue. WSP-9376 was discovered as an HCV helicase inhibitor (IC50 = 20 uM) in our laboratory through computational virtual screening using the DOCK program. Coincidentally, this compound was found as an HCV NS5B polymerase inhibitor (IC50 = 44.5 uM) as well, thus being selected as our lead. When it comes to both potency and selectivity toward HCV, NS5B RNA-dependent RNA polymerase (RdRp) can be a proper target. Since it is essential for HCV RNA polymerization and there is no functional counterpart in mammalian cells. Five binding sites of NS5B, four allosteric binding sites and the active site, are commonly reported. Most of the active site inhibitors belong to nucleoside analogues (substrate-like) or pyrophosphate-mimics (product-like). On the contrary, numerous classes of structurally diversified allosteric inhibitors have been developed. By employing scaffold hopping strategies, four series of compounds were designed whereas only one was fulfilled in synthesis, i.e. 3-arylmethylene-1H-quinoline-2,4-diones. Among them, compound 44b is the most potent NS5B inhibitor with an IC50 of 8.4 uM against NS5B. Albeit there is only slight improvement in the inhibitory activity of 44b compared with the lead, it is more important that we have identified this core structure for the development of new NS5B inhibitor, even if the structure differs a lot from that of WSP-9376. Moreover, the binding site of this series of compounds may be the active site, since compound 44b has been shown to have influence to some extent on the substrates of NS5B. In other words, this is probably another series of active site inhibitors distinguished from those published previously.